As to the current human society is becoming increasingly complex in structure and mechanism, so that people undergo increasing stresses of various kinds. In such an ever-changing society, the number of people suffering from mental disorder, particularly depression and anxiety neurosis are increasing, posing a big social problem.
Unlike the typical depression seen in the past, depression appearing currently is relatively slight and tends to become chronic, in many cases. Depression is often difficult to distinguish from neurosis and tends to become chronic. It is reported that most of the patients of chronic depression have neurosis as well and that the number of depression patients is increasing more and more in recent years (cf. Japanese Journal of Clinical Psychiatry, Vol. 21, No. 4, pp. 691-695, 1992).
Thus, the features of mental disorder are becoming more complex as the structure and mechanism of society become complex. The following two facts are pointed out as the recent major changes in the features of metal disorder.
(1) In neurosis, those neuroses are increasing which show depressive syndrome and which are difficult to distinguish from depression.
(2) Among the patients which have been judged to have neurosis, patients of slight depression are included. Among, in particular, the patients which have been judged to have neurosis because of their anxiety attack and expectation fear, patients of slight depression are included at a fairly high ratio (cf. Japanese Journal of Clinical Psychiatry, Vol. 21, No. 4, pp. 691-695, 1992).
According to a clinical research (cf. "Anxious Depression" edited by Racagni G. Smeraldi, Raven Press, N.Y., 1987), analysis of the symptoms of the patients who had been judged to have serious depression, indicated that the symptoms comprised worry of intermediate level (72%), psychological anxiety (62%), physical anxiety (of autonomic nervous system and muscle system) (42%), fear attack (29%), fear symptom (19%) and obsessive-compulsive symptom (1.2%). Patients of depression include patients of anxiety symptom at a high ratio.
Mental disorder which show complex and diversified symptoms as mentioned above, are currently treated, in many cases, with an antidepressant, an antianxiety agent or a combination thereof, depending upon the symptoms. Such treatment is effective in some cases but is said to be insufficient in most cases. Conventional antidepressants are effective for endogeneous depression, but are not sufficiently effective for character-originated depression or highly neurotic depression (cf. Journal of Neuropsychopharmacology, Vol. 9, No. 4, pp. 279-285, 1987). Use of antianxiety agent by patients who show anxiety symptom on the surface while actually having a depressive phase, prolongs the depression in some cases (cf. Japanese Journal of Clinical Psychiatry, Vol. 21, No. 4, pp. 691-695, 1992). Use of antidepressant based on the indiscreet judgement by clinical department other than psychiatry department, may overlook suicidal ideation and induce the prolongation of depression (cf. Journal of Neuropsychopharmacology, Vol. 9, No. 4, pp. 279-285, 1987).
Conventional antidepressants have problems; that is, (1) they show no immediate effect and need to be administered continuously for at least 2 weeks, (2) they have undesirable side effects such as anti-cholinergic effect and the like and (3) they are ineffective in some cases (effective ratio: 65%) (cf. Journal of Neuropsychopharmacology, Vol. 11, No. 10, pp. 753-761, 1989). Conventional antianxiety agents have problems; that is, (1) they have side effects such as excessive sedation, somnolence, muscle relaxation and the like and (2) there often appear serious adverse symptoms such as dependency, abstinence symptom, memory impairment and the like (cf. Journal of Neuropsychopharmacology, Vol. 11. No. 9, pp. 709-719, 1989).
Single or combination use by patients, of antidepressant and antianxiety agent which, as mentioned above, have many side effects and many adverse effects and are said to be ineffective to the core symptoms of mental disorder, is considered to produce antinomy in the treatment of mental disorder. Hence, if there is developed a medicine which tackles the root cause of mental disorder and which shows both an anti-depression activity and an anti-anxiety activity, it will solve the above-mentioned problems associated with the treatment of mental disorder.
Compounds having chemical structures similar to those of the benzylamine derivatives of the present invention are disclosed in PCT International Applications WO 90/14334 (Publication Date: Nov. 29, 1990), WO 93/07113 (Publication date: Apr. 15, 1993), WO 91/09594 (Publication Date: Jul. 11, 1991) and WO 93/00313 (Publication Date: Jan. 7, 1993). Particularly in WO 91/09594 and WO 93/00313 are disclosed compounds represented by the following general formula: ##STR2## wherein: Ar is aryl or heteroaryl wherein aryl or heteroaryl can be substituted by hydrogen, halogen such as chloro, fluoro, bromo or iodo, CF.sub.3, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 dialkoxymethyl, C.sub.1 -C.sub.6 alkyl, cyano, C.sub.3 -C.sub.15 dialkylaminoalkyl, carboxy, carboxamino, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 haloalkylthio, allyl, aralkyl, C.sub.3 -C.sub.6 cycloalkyl, aroyl, aralkoxy, C.sub.2 -C.sub.6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, an aryl ring fused to a substituted benzene ring, a substituted aryl ring fused to a benzene ring, a heteroaryl ring fused to a benzene ring, a substituted heteroaryl ring fused to a benzene ring, C.sub.3 -C.sub.6 heterocycloalkyl, a C.sub.3 -C.sub.6 heterocycloalkyl ring fused to a benzene ring, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfonyl, C.sub.1 -C.sub.6 haloalkylsulfonyl, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 haloalkylsulfinyl, arylthio, C.sub.1 -C.sub.6 haloalkoxy, amino, C.sub.1 -C.sub.6 alkylamino, C.sub.2 -C.sub.15 dialkylamino, hydroxy, carbamoyl, C.sub.1 -C.sub.6 N-alkylcarbamoyl, C.sub.2 -C.sub.15 N,N-dialkylcarbamoyl, nitro or C.sub.2 -C.sub.15 dialkylsulfamoyl;
R is hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 R.sup.1 is selectively from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, amino, C.sub.1 -C.sub.6 alkylamino and .dbd.O (a double bond oxygen); or PA1 R and R.sup.1 together form a morpholino ring; PA1 n is 0-5; PA1 W is --(CH.sub.2).sub.p -- or --H H-- wherein p is 1-3; PA1 X is --(CH.sub.2).sub.q -- wherein q is 1-6, --(CH.sub.2).sub.r --C.tbd.C--(CH.sub.2).sub.r -- wherein each r is 0-3, --(CH.sub.2).sub.r --CH.dbd.CH--(CH.sub.2).sub.r --, ##STR3## --(CH.sub.2).sub.r --Y--(CH.sub.2).sub.r -- wherein Y is O or S, or C.sub.1 -C.sub.6 alkyl (wherein Z is hydrogen); and
Z is hydrogen, aryl, an aryl-substituted carboxylic acid group, heteroaryl or cycloalkyl, wherein aryl, heteroaryl and cycloalkyl can be substituted by hydrogen, halogen such as chloro, fluoro, bromo or iodo, CF.sub.3, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 dialkoxymethyl, C.sub.1 -C.sub.6 alkyl, cyano, C.sub.3 -C.sub.15 dialkylaminoalkyl, carboxy, carboxamido, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 haloalkylthio, allyl, aralkyl, C.sub.3 -C.sub.6 cycloalkyl, aroyl, aralkoxy, C.sub.2 -C.sub.6 carboxylic acyl, acyl, substituted aryl, heteroaryl, substituted heteroaryl, an aryl ring fused to a substituted benzene ring, a substituted aryl ring fused to a benzene ring, a heteroaryl ring fused to a benzene ring, a substituted heteroaryl ring fused to a benzene ring, C.sub.3 -C.sub.6 heterocycloalkyl, a C.sub.3 -C.sub.6 heterocycloalkyl ring fused to a benzene ring, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfonyl, C.sub.1 -C.sub.6 haloalkylsulfonyl, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 haloalkylsulfinyl, arylthio, C.sub.1 -C.sub.6 haloalkoxy, amino, C.sub.1 -C.sub.6 alkylamino, C.sub.2 -C.sub.15 dialkylamino, hydroxy, carbamoyl, C.sub.1 -C.sub.6 N-alkylcarbamoyl, C.sub.2 -C.sub.15 N,N-dialkylcarbamoyl, nitro, C.sub.2 -C.sub.15 dialkylsulfamoyl or an ortho methylenedioxy group.
According to said two literatures, the compounds of the above general formula are useful as a sigma-receptor ligand and can be used as a drug for schizophrenia or other psychosis, or for the treatment of central nervous system diseases, drug abuse, gastrointestinal diseases, hypertension, migrane, peritonsilitis, depression, etc.
Thus, the above-mentioned literatures disclose compounds having chemical structures similar to those of the present benzylamine derivatives, but do not disclose the present benzylamine derivatives per se.
Under the above situation, the present inventors made an extensive study and found out that the benzylamine derivatives represented by the above general formula (1) and their salts have both an anti-depression activity and an anti-anxiety activity and are effective as an excellent anti-depression and anti-anxiety drug. The present invention has been completed based on the finding. The benzylamine derivatives and their salts according to the present invention are characterized in that they are effective for amelioration of consciousness disturbance as well as for the treatment of obsessive-compulsive neurosis.